The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2011-10, Vol.99 (4), p.671-675
• Main Authors: Navani, Dipesh M., Sirohi, Sunil, Madia, Priyanka A., Yoburn, Byron C.
• Format: Article
• Language: English
• Subjects: 6β-naltrexol; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Constitutive receptor activity; Dependence; Dose-Response Relationship, Drug; Inverse opioid agonist; Male; Medical sciences; Mice; Morphine; Morphine Dependence - psychology; Naltrexone; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Narcotic Antagonists - pharmacology; Narcotics; Neutral opioid antagonist; Receptors, Opioid - agonists; Receptors, Opioid - drug effects; Receptors, Opioid - physiology; Substance Withdrawal Syndrome - drug therapy; Substance Withdrawal Syndrome - psychology; Withdrawal
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2011.06.025

On the basis of efficacy, opioid antagonists are classified as inverse opioid agonists (e.g. naltrexone) or neutral opioid antagonists (e.g. 6β-naltrexol). This study examined the interaction between naltrexone and 6β-naltrexol in the precipitated opioid withdrawal syndrome in morphine dependent mice. Furthermore, the possible contribution of constitutive opioid receptor activity to precipitated withdrawal was evaluated using increasing levels of morphine dependence. In the first experiment, low doses of 6β-naltrexol antagonized naltrexone precipitated withdrawal while high doses acted additively. All doses of naltrexone increased 6β-naltrexol's potency to precipitate withdrawal. The next experiment examined changes in antagonist potency to precipitate withdrawal with increasing morphine dependence. Mice were exposed to morphine for 1–6days and then withdrawal was precipitated. Naltrexone was more potent than 6β-naltrexol at all the time points. The ED50 of both drugs decreased at the same rate suggesting that increased dependence produced no change in constitutive opioid receptor activity. Taken together these results indicate that the functional efficacy of 6β-naltrexol is dose-dependent and that constitutive opioid receptor activity did not change as opioid dependence increased from 1 to 6days. ► Naltrexone is an inverse agonist and 6β-naltrexol is a neutral opioid antagonist. ► Naltrexone and 6β-naltrexol precipitate opioid withdrawal. ► Naltrexone acts additively with 6β-naltrexol to precipitate withdrawal. ► 6β-naltrexol dose-dependently decreases or increases the potency of naltrexone. ► Constitutive opioid receptor activity may not increase with opioid dependence.